Zoledronic Acid in Acute Spinal Cord Injury

Zoledronic Acid to Prevent Bone Loss After Acute Spinal Cord Injury

Maintenance of bone mass following spinal cord injury (SCI) is essential to fracture prevention and the associated morbidity of bed rest and further secondary complications. Intravenous (IV) zoledronic acid (ZA) is an FDA-approved drug that has been shown to be more effective than other agents in reducing bone mass resorption and leg fractures in post-menopausal women, but has not been studied in patients with acute SCI. This will be a randomized, double-blind, placebo-controlled trial of IV ZA to prevent bone loss early after SCI. Up to 48 subjects will be randomized to receive a one-time dose of 5 mg of IV ZA versus placebo within 21 days of an SCI.

Study Overview

• Status: Completed
• Conditions: Spinal Cord Injury
• Intervention / Treatment: Drug: Zoledronic acid; Drug: normal saline 0.9%

Detailed Description

Maintenance of bone mass following spinal cord injury (SCI) is essential to fracture prevention and the associated morbidity of bed rest and further secondary complications. Intravenous (IV) zoledronic acid (ZA) has been shown to be more effective than other agents in reducing bone mass resorption and fracture of the legs in post-menopausal women, but has not been studied in acute spinal cord injury. Two previous studies of ZA in persons with subacute SCI, while promising, were inconclusive. As stated in the long range plan of the National Institute on Disability and Rehabilitation Research (NIDRR), one goal in the area of health and function is to "focus on the onset of new conditions…exacerbation of existing conditions, or the development of coexisting conditions." This study is intended to demonstrate reduction in loss of bone mass at the hip and knee regions in acute SCI in a rigorous study of sufficient size to determine effectiveness of our intervention.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University and Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ages 18-65, male or female
• Traumatic SCI with Neurological level C4-T10, American Spinal Injury Association (ASIA) Impairment Scale (AIS) A,
• Serum calcium level >7.0 mg/dL) at time of study drug administration
• Screening baseline serum 25-hydroxy (25-OH) vitamin D of at least 13 ng/ml
• No medical contraindication to supplemental vitamin D for participants whose levels are >13 ng/ml but sub-therapeutic (<32ng/ml)
• No medical contraindication to supplemental calcium
• Weight under 300 pounds, which is the maximum permitted on the dual-energy X-ray absorptiometry (DXA) scanner

Exclusion Criteria:

• Ventilator-dependent individuals
• Chronic steroid use (defined as >6 months)
• Rheumatoid disease with use of prior disease modifying anti-rheumatic drugs (DMARDs) affecting bone density
• History of osteoporosis or of treatment for osteopenia or osteoporosis with bisphosphonates, or selective reuptake estrogen modifying agents
• Current use of medications* including bisphosphonates to treat osteoporosis (*note that prior calcium or vitamin D use is not an exclusion criteria)
• History of more than one lower extremity osteoporosis-related fracture
• Chronic renal insufficiency, creatinine clearance < 35 ml/min, during screening
• End stage liver or kidney disease
• Medical conditions resulting in hypogonadal states that affect bone density
• Uncontrolled thyroid disease/thyrotoxicosis
• Hereditary or acquired metabolic bone disorder
• History of use of unfractionated heparin for >1 year
• History of selected antiseizure medications, specifically phenobarbital, phenytoin, carbamazepine, sodium valproate >1 year
• Acute or chronic bilateral lower extremity fractures involving tibia or femur, with placement of surgical hardware in any areas of above locations
• Severe hypotension requiring use of intravenous blood pressure agents such as dopamine, norepinephrine or phenylephrine. Exception may allow for patients on pressors who arm experiencing hypotension as they acclimate to upright posture.
• Inability to provide informed consent and understand the consent process
• Facial fractures requiring oral surgery
• Dental surgery or oral maxillofacial surgery within 2 weeks of anticipated study drug administration
• Pregnancy present on admission
• Vitamin D deficiency on admission testing (serum 25-OH D reported as < 13 ng/mL)
• Patients with an established reaction to, or history of, anaphylactic shock to aspirin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zoledronic Acid 5 mg IV infusion; Single infusion of 5 mg intravenous zoledronic acid given within 21 days of acute traumatic spinal cord injury.	Drug: Zoledronic acid; 5 mg zoledronic acid infused intravenously over two hours (2.5mg per hour), given only once, within 21 days of acute traumatic spinal cord injury.; Other Names: Reclast
Placebo Comparator: normal saline 0.9%; Infusion of normal saline of equivalent volume to reconstituted zoledronic acid, given only once and run over 2 hours, to occur within 21 days of acute traumatic spinal cord injury.	Drug: normal saline 0.9%; Infusion of equivalent volume of 0.9% normal saline to that of the reconstituted zoledronic acid, given only once over two hours, occurring within 21 days of acute traumatic spinal cord injury; Other Names: normal saline; 0.9% saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Areal Bone Mineral Density at Hip	Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 4 months compared to baseline. This will compare aBMD at the hip.	4 months
Change in Areal Bone Mineral Density at Knee	Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 4 months compared to baseline. This will compare aBMD at the distal femur and proximal tibia.	4 months
Change in Areal Bone Mineral Density at Hip	Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 12 months post-injury compared to baseline. This will compare aBMD at the hip.	one year
Change in Areal Bone Mineral Density at Knee	Percent change in areal bone mineral density (aBMD) assessed by dual energy X-ray absorptiometry (DXA) at 12 months post-injury compared to baseline. This will compare aBMD at the distal femur and proximal tibia.	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Biomarkers of Bone Resorption (sCTX)	Change in sCTX from baseline to 1- and 4-months post intervention and 12-months post-injury.	1 month, 4 months, 12 months
Change in Biomarkers of Bone Formation (P1NP)	Change in serum P1NP from baseline to 1- and 4-months post intervention.	1 month, 4 months
Safety and Tolerability of Zoledronic Acid	Assessment of the safety and tolerability of zoledronic acid in the acute spinal cord injury population. This will be done by examination reportable adverse events including fevers, flu-like symptoms, GI upset as measures of safety and report of patient's willingness to have participate in physical therapy in the first week after receiving medication as a measure of tolerability	72-hours and 1 month post intervention.

Collaborators and Investigators

• Sponsor: Thomas Jefferson University
• Collaborators: Department of Health and Human Services
• Investigators: Principal Investigator: Christina V Oleson, MD, Thomas Jefferson University

Publications and helpful links

General Publications

• Oleson CV, Marino RJ, Formal CS, Modlesky CM, Leiby BE. The effect of zoledronic acid on attenuation of bone loss at the hip and knee following acute traumatic spinal cord injury: a randomized-controlled study. Spinal Cord. 2020 Aug;58(8):921-929. doi: 10.1038/s41393-020-0431-9. Epub 2020 Feb 13.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: July 6, 2012
• First Submitted That Met QC Criteria: July 12, 2012
• First Posted (Estimate): July 17, 2012

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: May 1, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: spinal cord injury; bone mineral density
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Spinal Cord Diseases; Wounds and Injuries; Spinal Cord Injuries; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: 11F.612

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO